Pre-eclampsia complicates roughly 2–8% of pregnancies and is a leading cause of maternal and perinatal mortality, with early-onset (<34 wk) disease carrying a long-term maternal cardiovascular-disease hazard of ~2.5–3.0. This oracle estimates the causal reduction in pre-eclampsia incidence (early-onset focus) across established prevention (aspirin, calcium, exercise) and investigational mechanism-targeted therapy — DM199 (recombinant human KLK1). Hazard ratios are from named trials; DM199 is shown as an explicit mechanistic projection (no outcome trial). For education, not individual medical advice.
Tick the interventions to combine. Each shows its trial effect estimate, 95% confidence interval (CI), E-value, mechanism, and citation. ★ = in the current Pareto effective set but not yet ticked.
Headline is the front-door estimate: shared Endo overlap removed via dose-response saturation; residual direct-effect overlap removed via the eigenvalue model at ρ̄.
Under monotonicity + exogeneity (E-value bounds the exogeneity assumption).
Faithful causal directed acyclic graph (DAG). Preventive interventions act largely through the shared mediator endothelial function / placental perfusion (spiral-artery remodelling, NO / PGI2 / EDHF), lowering placental-vascular resistance and thence pre-eclampsia incidence (Y), with a downstream edge to long-term maternal CVD. DM199 acts directly on the mechanism (recombinant KLK1 → bradykinin → NO / PGI2 / EDHF). Named confounders — pre-pregnancy metabolic/vascular risk, primiparity, prior PE, angiogenic balance (sFlt-1/PlGF) — open back-door paths (adjusted). Shared endothelial dysfunction confounds the PE→CVD edge. Mediator cascade: interventions attach to the node they act on (antiplatelet → endothelial / → metabolic → anticoagulation), which converge on the disease state and thence the endpoint — drawing the intermediate mediators explicitly is what exposes d-separation and per-channel saturation.
Eigenvalue diagnostics for the selected interventions under an equicorrelation matrix (off-diagonal ρ̄). A large λmax relative to k signals redundancy; n_eff is the effective number of independent interventions actually contributing.
On mechanistic grounds ρ̄ ≈ 0.30 is defensible: aspirin, calcium, exercise, L-arginine and DM199 converge on the same endothelial/placental-perfusion mediator, so stacking them is partly redundant. ρ̄ is user-adjustable because their entry points differ (antiplatelet vs NO-substrate vs direct KLK1 vs smooth-muscle calcium), and LMWH sits largely off the effective pathway. Most of the overlap is now handled structurally by the mediator nodes (same-node substitutes saturate); ρ̄ governs only the residual correlation among direct effects.
Minimum-effective-set analysis. Set a target combined risk reduction; the model finds the smallest set of interventions — accounting for front-door mediator overlap — that reaches it, and highlights them. If the target exceeds what all interventions together can achieve, the full set is shown (never an empty one). "Apply" ticks exactly that set.
Monte Carlo propagation. Each selected intervention's log-effect is sampled from a normal distribution implied by its 95% CI; samples are combined with the same eigenvalue overlap discount. 5,000 draws.
Intervening on the selected set S with Pearl's do-operator (setting the interventions, not merely observing them). Contrast against do(∅) = no intervention.
For each intervention: "if not for this one, the combined front-door effect would be…". Isolates each intervention's marginal causal contribution after mediator-overlap removal, so shared-pathway agents are not double-credited.
| If not for… | HR without it | HR with full set | marginal RRR lost |
|---|
One-at-a-time sensitivity. Each intervention's effect is swung across its 95% confidence interval (others held at point estimate); the bar is the resulting swing in the combined front-door effect. A long bar means the combined estimate leans heavily on that single trial's precision.
Front-door (mediation) decomposition. Each log-effect is split into an endothelial/perfusion-mediated (indirect) and a mediator-independent (direct) part. Indirect parts are pooled through the mediator with dose-response saturation, removing the mediator cross-correlation; direct parts keep the residual eigenvalue correlation at ρ̄. DM199’s effect is almost entirely mediator-directed by design — which is precisely why, with only surrogate data, a high mediated fraction paired with an unproven outcome is the graph’s central caution. Here mediated effects are pooled WITHIN each cascade node (dose-response saturation of substitutes) and composed in SERIES across nodes (d-separated channels), with the per-node reductions reported so the channel structure is visible.
| Intervention | HR | %Perf↑ | med-frac | indirect log | direct log |
|---|
Which % of cross-correlation is appropriate? Not one number. The mediator overlap is fixed empirically by the Endo saturation (currently removing — of the summed mediated effect when interventions are stacked). Note a domain caveat: DM199 and LMWH illustrate the two failure modes — DM199 moves the mediator strongly on surrogates but has no outcome trial; LMWH has a mechanistic story but a near-null hard-outcome result. Neither should be read as an established preventive.
Front-door caveat (antithesis): textbook front-door identification requires an unconfounded mediator→outcome edge; here pre-pregnancy endothelial/metabolic dysfunction confounds both the mediator→PE and the PE→CVD edges, and effect sizes are strongly population-conditional (early-onset vs term; calcium-replete vs deplete). DM199’s figure is a projection from Phase-2 surrogates, not an outcome estimate.
Select interventions to generate a plain-language summary.